chr17-3481793-A-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000049.4(ASPA):c.427A>T(p.Ile143Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I143T) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000049.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ASPA | NM_000049.4 | c.427A>T | p.Ile143Phe | missense_variant | 2/6 | ENST00000263080.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASPA | ENST00000263080.3 | c.427A>T | p.Ile143Phe | missense_variant | 2/6 | 1 | NM_000049.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000423 AC: 1AN: 236296Hom.: 0 AF XY: 0.00000784 AC XY: 1AN XY: 127626
GnomAD4 exome AF: 6.93e-7 AC: 1AN: 1443698Hom.: 0 Cov.: 29 AF XY: 0.00000139 AC XY: 1AN XY: 717902
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Spongy degeneration of central nervous system Pathogenic:3Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 14, 2024 | - - |
Uncertain significance, flagged submission | clinical testing | Counsyl | Dec 05, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 143 of the ASPA protein (p.Ile143Phe). This variant is present in population databases (rs199565861, gnomAD 0.003%). This missense change has been observed in individual(s) with Canavan disease (PMID: 16854607). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372307). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ASPA protein function. Experimental studies have shown that this missense change affects ASPA function (PMID: 22850825). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 14, 2015 | The I143F variant has been reported previously in association with Canavan disease (Zeng et al., 2006). Functional analysis of the I143F variant found that it is associated with 1% residual aspartoacylase activity (Zano et al., 2013). Therefore we interpret this variant to be pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at